My research group focusses on translational research in patients with autoimmune rheumatic disease. We have been studying regulatory (immune suppressing) T cells in these diseases in an effort to harness/manipulate these lymphocytes to treat patients more effectively. One approach we have been taking is to use novel biologic therapies as a tool to understand the aberrant immune responses found in patients with autoimmunity (1). Over the last few years there has been a re-emphasis on research into the processes of the human immune system. This has been partly due to the increasingly sophisticated tools available to dissect out immunological processes.

Our results so far indicate that regulatory T cells are defective in patients with rheumatoid arthritis. We have identified a potential molecular explanation for this defect (2), which could represent a novel therapeutic target. In addition, after anti-TNF therapy we have observed the induction of an "adaptive" regulatory T cell population, which suppresses via different mechanisms to the "natural" regulatory T cells found in healthy individuals (3). Partly based on these results, we are developing a biomarker to predict response to anti-TNF therapy, which will enable this treatment to be given to only those patients that will respond. Our long-term goal is to define the cellular and molecular mechanisms that switch off inflammation.

On going projects include:

1. The balance between pro-inflammatory (e.g. Th17) and regulatory T cell subsets in patients with autoimmune rheumatic disease e.g. rheumatoid arthritis and psoriatic arthritis.
2. The immunological consequences of B cell depletion in patients with systemic lupus erythematosus particularly with regard to immunoregulation.
3. The role of natural IgM in the immune response and how it modulates autoimmunity. Natural IgM is known to be important in clearing apoptotic cells, which are central to the initiation of autoimmunity.
4. Abnormal signalling in conventional and regulatory T cells (4).
5. We have been studying the potential for B cells to regulate the immune response. These regulatory B cells secrete IL-10 and can dampen autoimmunity. Currently we are investigating their function in animal models of disease but also attempting to identify their phenotype in patients with autoimmunity. This work is in collaboration with Dr Claudia Mauri.


References:


1. Ehrenstein, M.R., and C. Mauri. 2007. If the treatment works, do we need to know why?: the promise of immunotherapy for experimental medicine. J Exp Med 204:2249-2252.
2. Flores-Borja, F., E. Jury, C. Mauri, and M.R. Ehrenstein. In press. Defects in CTLA-4 are associated with abnormal regulatory T cell function in rheumatoid arthritis. Proc Natl Acad Sci U S A
3. Nadkarni, S., C. Mauri, and M.R. Ehrenstein. 2007. Anti-TNF-{alpha} therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-{beta}. J Exp Med 204:33-39.
4. Jury, E.C., D.A. Isenberg, C. Mauri, and M.R. Ehrenstein. 2006. Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus. J Immunol 177:7416-7422.